Introduction
Catheter ablation has been established as an important therapy for
atrial fibrillation (AF). The prevalence of left atrial low-voltage
areas (LVAs) is strongly associated with the recurrence of atrial
tachyarrhythmias following catheter ablation, and the addition of guided
ablation of LVAs improves procedural outcomes compared to pulmonary vein
(PV) isolation alone. 1,2,3,4The ability to predict the presence of LVAs in advance of ablation would
be useful in considering ablation indications and planning ablation
methods. A preliminary study investigated a risk score named
DR-FLASH,5 which is composed of several clinical risk factors,
including age >65 years and renal dysfunction
(estimated glomerular filtration
rate <90 mL/min/1.73m2). In countries with
an aging society, however, these cut-off values for elderly age
(>65 years) and renal dysfunction (estimated glomerular
filtration rate <90 mL/min/1.73m2) appear so
lenient that the score does not appropriately represent the risk of LVA
presence.
Hence,
we sought a new risk score which allows the prediction of LVAs in
elderly patients and contemporary clinical settings.
The objective of this study was to explore predictors of LVA prevalence
and establish a new clinical risk score for predicting the prevalence of
LVAs in patients undergoing atrial fibrillation ablation.
Methods
Patients From October 2014 to December 2018, 1004 consecutive patients undergoing
initial ablation for AF using Carto 3 (Biosense Webster, Inc., Diamond
Bar CA, USA), Ensite NavX (St. Jude Medical, Inc., St. Paul MN, USA) or
Rhythmia (Boston Scientific, Boston MA, USA) were retrospectively
enrolled at our hospital. Patients who could not undergo voltage mapping
were excluded. Other exclusion criteria were age <20 years,
left atrial thrombus, and prior catheter ablation of AF. This study
complied with the Declaration of Helsinki. Written informed consent for
ablation and the use of data in this study was obtained from all
patients, and the protocol was approved
by
our institutional review board.Catheter ablation procedureElectrophysiological studies and catheter ablation were performed under
intravenous sedation with dexmedetomidine or propofol, with the latter
performed by four experienced operators (M.M, T.K, A.S, Y.M). From
October 2014 to March 2016, radiofrequency catheter ablation
was
performed for all patients. From March 2016 to December 2018, in
general, cryoballoon ablation was performed for paroxysmal AF and for
persistent AF of short standing. Patients with common PVs or a large PV
diameter underwent radiofrequency catheter ablation.
In cryoballoon ablation, an Arctic Front Advance cryoballoon catheter
with a 28-mm balloon size (Medtronic, Inc., Minneapolis MN, USA) was
passed into each PV under guidance by fluoroscopy and the 3-D mapping
system. After confirming PV occlusion by pulmonary venography,
cryoablation commenced and continued for 180 s, during which individual
PVs were isolated. If LA–PV conduction persisted after cryoballoon
ablation, an additional touch-up ablation was performed using an
open-irrigated Thermocool SmartTouch (Biosense Webster) or FlexAbility
(St. Jude Medical) linear ablation catheter with a 3.5-mm tip.
In radiofrequency catheter ablation, circumferential ablation around
both ipsilateral PVs was performed using an open-irrigated Thermocool
SmartTouch (Biosense Webster) or FlexAbility (St. Jude Medical) linear
ablation catheter via an Agilis or Swartz Braided SL0 Transseptal
Guiding Introducer Sheath (St. Jude Medical). Radiofrequency energy was
applied for 30 s at each site using a maximum temperature of 42°C,
maximum power of 35 W, and flow rate of 17 mL/min. PV isolation was
considered complete when the 20-pole circular catheter no longer
recorded any PV potentials.
Additional
ablation was also performed for spontaneous atrial flutter or flutter
induced by atrial burst stimuli, and for any AF triggers originating
from non-PV foci induced by isoproterenol infusion.
Voltage mapping Following PV isolation, detailed voltage mapping was performed using a
bipolar 3.5-mm tip catheter or multi-electrode mapping catheter during
sinus rhythm or with pacing from the right atrium. Mapping points were
acquired to fill all color gaps on the voltage map using the
electroanatomical mapping system. Respective fill and color
interpolation thresholds were 15 mm and 23 mm using Carto 3 (Biosense
Webster) and 20 mm and 7 mm using Ensite NavX (St. Jude Medical). Using
Rhythmia (Boston Scientific), interpolation threshold was 5 mm and
confidence mask was 0.03 mV.
Sites at which LVAs were recorded were then evaluated by high-density
mapping to precisely delineate their extent, using the confidence module
with the Carto 3 system and Ensite Automap with Ensite NavX. Adequate
endocardial contact was confirmed
by
distance to the geometry surface and stable electrograms. Each acquired
point was classified according to the peak-to-peak electrogram as
follows: >0.5 mV, healthy; <0.5 mV, LVAs, with
the band pass filter was set at 30 to 500 Hz. LVAs were defined as
regions with ≥5 cm2 low-voltage points across the
total surface area of the left atrium. The target number of mapping
points was ≥100 with the 3.5-mm tip catheter and ≥1000 with the
multi-electrode mapping catheter throughout the left atrium.
Patient followup Rhythm outcomes were followed for 24 months. Followup was performed as a
part of routine visits, usually conducted every 3 months. Each routine
visit included 12-lead electrocardiogram, while Holter
electrocardiography was performed 6 months after the procedure. AF
recurrence was defined as atrial tachyarrhythmias lasting
>30 s at ≥90 d after the procedure.
Statistical methods Continuous data are expressed as mean ± standard deviation. Categorical
data are presented as absolute values and percentages. Tests for
significance were conducted using the unpaired or paired t-test
for continuous variables and the chi-squared test for categorical
variables. Receiver operating characteristic curve analysis was
conducted between the clinical factors and prevalence of LVAs.
Kaplan-Meier analysis and the log-rank test were used to investigate the
association between the recurrence of atrial tachyarrhythmia and
prevalence of LVAs. Univariate and multivariate logistic regression
analyses were used to determine clinical factors associated with the
prevalence of LVAs, wherein variables with a P value ≤0.05 in the
univariate models were included in the multivariate analysis. A new risk
score was obtained as the total number of independent predictors
identified by multivariate analysis.
All analyses were performed using commercial software (SPSS ™, SPSS,
Inc., Chicago IL, USA).
Results
Patient characteristics One thousand and four patients
undergoing
atrial fibrillation ablation were enrolled. PVI was successfully
completed in all patients, using Carto 3 in 822 (82%), Ensite NavX in
159 (16%) and Rhythmia in 23 (2%). Patient characteristics are shown
in Table 1.
Voltage mapping Left atrial voltage mapping was completed in all cases, with a median of
681 (119-1222) acquired mapping points. LVAs were identified in 206
(21%) cases. Procedural characteristics between the presence and
absence of LVAs are compared in Table 2.
Predictors of LVAs prevalence Patients with LVAs were significantly older, more frequently female, and
had a higher prevalence of persistent AF, diabetes mellitus,
thromboembolism, and vascular disease than those without. In addition,
patients with LVAs had lower hemoglobin, lower body mass index, lower
estimated glomerular filtration rate, higher brain natriuretic peptide,
higher N-terminal pro-brain natriuretic peptide, higher left ventricular
mass index, higher left atrial diameter, higher E/e’, and longer
deceleration time than those without. On multivariate analysis,
independent predictors of LVA prevalence were female sex, persistent AF,
age ≥70 years, elevated brain natriuretic peptide ≥100 pg/ml or
N-terminal pro-brain natriuretic peptide ≥400 pg/ml, and diabetes
mellitus (Table 3).
New clinical risk score for LVAs prevalence The total number of independent predictors identified by multivariate
analyses above - female sex, persistent AF, age ≥70 years, elevated
brain natriuretic peptide ≥100 pg/ml or N-terminal pro-brain natriuretic
peptide ≥400 pg/ml, and diabetes mellitus - was then used to devise a
new clinical risk score, which we termed the SPEED score. LVAs were more
frequent in patients who had a higher SPEED score (Figure 1, Figure 2),
and the prevalence of LVAs increased with each additional SPEED score
point (odds ratio 2.4 [95% confidence interval 2.0-2.8], p
<0.01). In patients with LVAs, the median total area of LVAs
classified by SPEED score were 2.6 (1.7-3.1) cm2 (0
point), 4.8 (2.4-15.3) cm2 (1 point), 5.4 (2.9-9.7)
cm2 (2 points), 7.3 (3.6-14.8) cm2(3 points), 11.7 (6.0-21.9) cm2 (4 points) and 10.2
(6.9-25.6) cm2 (5 points). Receiver operating
characteristic curve analysis revealed that the SPEED score was a good
predictor of LVAs (Figure 3, area under the curve, 0.742).
AF recurrence in LVAs prevalence During the 24-month study period, 277 (28%) patients developed AF
recurrence. Freedom from recurrence was significantly lower in patients
with LVAs than in those without (Figure 4), and was significantly lower
in patients with a high SPEED score than in those with a low score
(Figure 5).
Discussion
In
this study of 1004 patients undergoing initial AF ablation, we found
that LVAs were present in 21% of the total study population.
Independent predictors of LVAs were female sex, persistent AF, age ≥70
years, elevated brain natriuretic peptide ≥100 pg/ml or N-terminal
pro-brain natriuretic peptide ≥400 pg/ml, and diabetes mellitus. Using
the SPEED score, calculated as the total number of independent
predictors in each patient, LVAs were more frequent in patients with a
higher SPEED score. These findings suggest that the SPEED score
accurately predicts the prevalence of LVAs in patients undergoing
ablation for AF.
Predictors of LVAs prevalence We identified the following as independent predictors of LVAs: female
sex, persistent AF, age ≥70 years old, elevated brain natriuretic
peptide ≥100 pg/ml or N-terminal pro-brain natriuretic peptide ≥400
pg/ml, and diabetes mellitus. The association between these predictors
and the prevalence of LVAs might be explained by atrial fibrosis and
decreased endocardial voltage.
Mechanisms
underlying the sex differences in atrial fibrosis have been
identified.6 On histological analysis of atrial tissue
obtained during cardiac surgery, females showed stronger expression of
CX 40 than males, which indicates remodeling–induced change in
connexins.7 In addition, fibrosis-related genes were
upregulated in post-menopausal woman with AF.8A number of studies have shown that AF itself induces atrial
fibrosis.9,10 Conversely, atrial fibrosis is required
to sustain AF, and
the
structural changes induced by AF in the atrium hinder termination of the
arrhythmia.11,12 Although the mechanisms of atrial
fibrosis are not precisely known, assessment of left atrial fibrosis by
cardiac magnetic resonance imaging showed that patients with persistent
AF had more late gadolinium-enhanced segments than those with paroxysmal
AF.13Aging
is another well-known factor associated with the promotion of myocardial
fibrosis and atrial remodeling.14 Senescence is
associated with interstitial fibrosis, which reduces the
capacity
to cope with cardiac stress.15 In addition, deposition
of collagen in the ventricles of the heart with aging has been shown in
animal models. 16,17 We set an age cut-off value of 70
years, which was previously defined as the lower limit of middle
age.18A previous study showed that atrial fibrosis also occurred as a result
of cardiac dysfunction, such as that which occurs in dilated
cardiomyopathy.19 Brain natriuretic peptide levels are
correlated with left ventricular end-diastolic pressure and left atrial
wall stress. 20,21 Left atrial wall stress is caused
by elevated left atrial pressure, which reflects volume or pressure
overload in the left ventricle and atrium. Left atrial wall stress can
lead to left atrial fibrosis. 21 We set a cut-off
value of brain natriuretic peptide and N-terminal pro-brain natriuretic
peptide of 100 pg/ml and 400 pg/ml, respectively, based on Japanese
guidelines for the diagnosis and treatment of acute and chronic heart
failure.22Diabetes mellitus is a cause of electrical remodeling and changes in
ionic currents, and additionally a cause of atrial structural
remodeling.23 Diabetes-related cardiac fibrosis is
associated with the accumulation of collagen,24 and
hyperglycemia may promote a fibrogenic phenotype in cardiomyocytes and
induce the synthesis and release of growth factors and cytokines that
induce fibroblast proliferation and activation.25New clinical risk score in LVA prevalenceBased on our findings, we established a new clinical risk score for
predicting the prevalence of LVAs, which we named the SPEED score. A
previous clinical risk score named
DR-FLASH
was based on diabetes mellitus, renal dysfunction (estimated glomerular
filtration rate <90 mL/min/1.73m2),
persistent form of AF, left atrial diameter >45 mm, age
>65 years, female sex, and hypertension.5 Although this score was shown to be valuable,
several limitations were noted. First, the score consists of seven
items, and scoring was complex. Second, two of these seven items
include
the majority of patients, namely estimated glomerular filtration rate
<90 mL/min/1.73m2 and age >65
years. Indeed, among our 1004 subjects, 958 (96%) had an estimated
glomerular filtration rate <90
mL/min/1.73m2, and 670 (67%) were older than 65
years. Having many items which most patients come under can hinder risk
stratification. Third, the only energy source of ablation used in the
DR-FLASH study cohort was radio frequency, and mapping catheter use was
limited. Finally, the cohort was relatively small, at about 240
patients.
The SPEED score improves these limitations: it has only five items and
is simple to score; the criterion that included the most patients -
elevated brain natriuretic peptide ≥100 pg/ml or N-terminal pro-brain
natriuretic peptide ≥400 pg/ml - accounted for fewer of our subjects
than did an estimated glomerular filtration rate <90
mL/min/1.73m2 and age >65 years; the
study cohort included more than 1000 patients; and the score can be
adapted for ablation with various energy sources, types of 3-D mapping,
and mapping catheters.
Additionally, receiver operating characteristic curve analysis revealed
that the SPEED score had a tendency to be better predictor of LVAs (area
under the curve, 0.742) than the DR-FLASH score (area under the curve,
0.694) in our subjects.
Clinical implications Previous studies showed that LVAs increase the risk of AF recurrence
following catheter ablation.4 Pre-procedural
prediction of LVAs using the SPEED score is simple and noninvasive.
Precise prediction of LVAs may influence indications for catheter
ablation and allow the operator to prepare for atrial ablation in
addition to PV isolation.
Limitations Several limitations of this study warrant mention. First, since we
performed voltage mapping using either bipolar 3.5-mm tip catheters or
multi-electrode mapping catheters, the distribution of LVAs might have
changed, given that multielectrode catheters produce smaller LVA
measurements than ablation catheters.26 Second, our
conduct of voltage mapping after the completion of PV isolation and in
the left atrium only might have influenced the prevalence of LVAs.
Third, LVA ablation was performed for only some patients, so the
association between SPEED score and AF recurrence could not be assessed
precisely. Finally, as this study was single center study, the
statistical analyses might have been influenced by the study population.
Conclusions
The SPEED score, based on the total number of the independent predictors
of female sex, persistent AF, age ≥70 years, elevated brain natriuretic
peptide ≥100 pg/ml or N-terminal pro-brain natriuretic peptide ≥400
pg/ml, and diabetes mellitus, accurately predicts the prevalence of LVAs
in patients undergoing ablation for AF.
Funding None declared
Conflicts of Interest None declared
References
- Verma A, Wazni OM, Marrouche NF, Martin DO, Kilicaslan F, Minor S,
Schweikert RA, Saliba W, Cummings J, Burkhardt JD, Bhargava M, Belden
WA, Abdul-Karim A, Natale A. Pre-existent left atrial scarring in
patients undergoing pulmonary vein antrum isolation: an independent
predictor of procedural failure. J Am Coll Cardiol 2005; 45:285–292.
- Masuda M, Fujita M, Iida O, Okamoto S, Ishihara T, Nanto K, Kanda T,
Shiraki T, Sunaga A, Matsuda Y, Uematsu M. Influence of underlying
substrate on atrial tachyarrhythmias after pulmonary vein isolation.
Heart Rhythm 2016; 13:870–878.
- Rolf S, Kircher S, Arya A, Eitel C, Sommer P, Richter S, Gaspar T,
Bollmann A, Altmann D, Piedra C, Hindricks G, Piorkowski C. Tailored
atrial substrate modification based on low-voltage areas in catheter
ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2014;
7:825–833.
- Masuda M, Fujita M, Iida O, Okamoto S, Ishihara T, Nanto K, Kanda T,
Tsujimura T, Matsuda Y, Okuno S, Ohashi T, Tsuji A, Mano T. Left
atrial low-voltage areas predict atrial fibrillation recurrence after
catheter ablation in patients with paroxysmal atrial fibrillation. Int
J Cardiol 2018; 257:97-101.
- Kosiuk J, Dinov B, Kornej J, Acou WJ, Schönbauer R, Fiedler L, Buchta
P, Myrda K, Gąsior M, Poloński L, Kircher S, Arya A, Sommer P,
Bollmann A, Hindricks G, Rolf S. Prospective, multicenter validation
of a clinical risk score for left atrial arrhythmogenic substrate
based on voltage analysis: DR-FLASH score. Heart Rhythm. 2015; 12:
2207-12.
- Odening KE, Deiß S, Dilling-Boer D, Didenko M, Eriksson U, Nedios S,
Ng FS, Roca Luque I, Sanchez Borque P, Vernooy K, Wijnmaalen AP,
Yorgun H. Mechanisms of sex differences in atrial fibrillation: role
of hormones and differences in electrophysiology, structure, function,
and remodelling. Europace. 2019; 21:366-376.
- Pfannmüller B, Boldt A, Reutemann A, Duerrschmidt N, Krabbes-Graube S,
Mohr FW, Dhein S. Gender-specific remodeling in atrial fibrillation?
Thorac Cardiovasc Surg. 2013; 61:66-73.
- Sánchez M, Secades L, Bordallo C, Meana C, Rubín JM, Cantabrana B,
Bordallo J. Role of polyamines and cAMP-dependent mechanisms on
5alpha-dihydrotestosterone-elicited functional effects in isolated
right atria of rat. J Cardiovasc Pharmacol. 2009; 54:310-318.
- Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation
begets atrial fibrillation: a study in awake chronically instrumented
goats. Circulation. 1995; 92:1954-1968.
- Everett TH 4th, Olgin JE. Atrial fibrosis and the mechanisms of atrial
fibrillation. Heart Rhythm. 2007; 4:S24-7.
- Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by
heart failure in dogs: atrial remodeling of a different sort.
Circulation. 1999; 100:87-95.
- Allessie MA. Atrial electrophysiologic remodeling: another vicious
circle? J Cardiovasc Electrophysiol. 1998; 9:1378-93.
- Lee DK, Shim J, Choi JI, Kim YH, Oh YW, Hwang SH. Left Atrial Fibrosis
Assessed with Cardiac MRI in Patients with Paroxysmal and Those with
Persistent Atrial Fibrillation. Radiology. 2019; 292:575-582.
- Burstein B, Nattel S. Atrial Fibrosis: Mechanisms and Clinical
Relevance in Atrial Fibrillation. J Am Coll Cardiol. 2008;
51:1162-1169.
- Lakatta EG. Cardiovascular regulatory mechanisms in advanced age.
Physiol Rev. 1993; 73:413-67.
- Pfeffer JM, Pfeffer MA, Fishbein MC, Frohlich ED. Cardiac function and
morphology with aging in the spontaneously hypertensive rat. Am J
Physiol. 1979; 237:H461–8.
- Liu CY, Liu YC, Wu C, Armstrong A, Volpe GJ, van der Geest RJ, Liu Y,
Hundley WG, Gomes AS, Liu S, Nacif M, Bluemke DA, Lima JAC. Evaluation
of age-related interstitial myocardial fibrosis with cardiac magnetic
resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of
Atherosclerosis). J Am Coll Cardiol. 2013; 62:1280-1287.
- Forman DE, Berman AD, McCabe CH, Baim DS, Wei JY. PTCA in the elderly:
the ”young-old” versus the ”old-old”. J Am Geriatr Soc. 1992;
40:19-22.
- Ohtani K, Yutani C, Nagata S, Koretsune Y, Hori M, Kamada T. High
prevalence of atrial fibrosis in patients with dilated cardiomyopathy.
J Am Coll Cardiol. 1995; 25:1162-1169.
- Maeda K, Tsutamoto T, Wada A, Hisanaga T, Kinoshita M. Plasma brain
natriuretic peptide as a biochemical marker of high left ventricular
end-diastolic pressure in patients with symptomatic left ventricular
dysfunction. Am Heart J 1998; 135: 825-832.
- Iwanaga Y, Nishi I, Furuichi S, Noguchi T, Sase K, Kihara Y, Goto Y,
Nonogi H. B-type natriuretic peptide strongly reflects diastolic wall
stress in patients with chronic heart failure: comparison between
systolic and diastolic heart failure. J Am Coll Cardiol. 2006;
47:742-8.
- Tsutsui H, Isobe M, Ito H, Ito H, Okumura K, Ono M, Kitakaze M,
Kinugawa K, Kihara Y, Goto Y, Komuro I, Saiki Y, Saito Y, Sakata Y,
Sato N, Sawa Y, Shiose A, Shimizu W, Shimokawa H, Seino Y, Node K,
Higo T, Hirayama A, Makaya M, Masuyama T, Murohara T, Momomura SI,
Yano M, Yamazaki K, Yamamoto K, Yoshikawa T, Yoshimura M, Akiyama M,
Anzai T, Ishihara S, Inomata T, Imamura T, Iwasaki YK, Ohtani T,
Onishi K, Kasai T, Kato M, Kawai M, Kinugasa Y, Kinugawa S, Kuratani
T, Kobayashi S, Sakata Y, Tanaka A, Toda K, Noda T, Nochioka K, Hatano
M, Hidaka T, Fujino T, Makita S, Yamaguchi O, Ikeda U, Kimura T,
Kohsaka S, Kosuge M, Yamagishi M, Yamashina A; Japanese Circulation
Society and the Japanese Heart Failure Society Joint Working Group.
JCS 2017/JHFS 2017 Guideline on Diagnosis and Treatment of Acute and
Chronic Heart Failure- Digest Version. Circ J. 2019; 83:2084-2184.
- Bohne LJ, Johnson D, Rose RA, Wilton SB1, Gillis AM1. The Association
Between Diabetes Mellitus and Atrial Fibrillation: Clinical and
Mechanistic Insights. Front Physiol. 2019; 10:135.
- Fischer VW, Barner HB, Larose LS. Pathomorphologic aspects of muscular
tissue in diabetes mellitus. Hum Pathol. 1984; 15:1127–1136.
- Russo I, Frangogiannis NG. Diabetes-associated cardiac fibrosis:
Cellular effectors, molecular mechanisms and therapeutic
opportunities. J Mol Cell Cardiol. 2016; 90: 84–93.
- Masuda M, Asai M, Iida O, Okamoto S, Ishihara T, Nanto K, Kanda T,
Tsujimura T, Matsuda Y, Okuno S, Tsuji A, Mano T. Comparison of
electrogram waveforms between a multielectrode mapping catheter and a
linear ablation catheter. Pacing Clin Electrophysiol. 2019;
42:515-520.